SUMMARY OF PRODUCT CHARACTERISTICS

for

Lovastatin Mylan tablets

1 NAME OF THE MEDICINAL PRODUCT

Lovastatin Mylan

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Lovastatin 20 mg and 40 mg

For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Tablets 20 mg: Pale blue, octagonal tablets marked “LV/20” on one side and “G” on the other, with score-line on one side. 40 mg: Green, octagonal tablets marked “LV/40” on one side and “G” on the other, with score-line on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications Severe cases of hypercholesterolaemia when dietary treatment does not have an adequate effect.

4.2 Posology and method of administration The patient should be placed on a standard cholesterol-lowering diet before being given lovastatin. This diet should be continued during treatment with lovastatin. Any cause for secondary hypercholesterolemia should be excluded before initiation of treatment.

HYPERCHOLESTEROLEMIA: The initial dose is generally 20 mg per day, given as a single dose with the evening meal. It has been shown that single daily doses given with the evening meal are more effective than the same dose given with breakfast, possibly because cholesterol synthesis takes place mainly at night. Patients with mild to moderate hypercholesterolemia may be treated with an initial dose of 10 mg lovastatin. Any dosage adjustments should be made at intervals of at least 4 weeks. A maximum of 80 mg should be given daily in a single dose or divided into 2 doses taken with breakfast and the evening meal. Two daily doses would appear to be more effective than one daily dose.

The dosage of lovastatin should be reduced if LDL-cholesterol levels drop below 75 mg/dL (1.94 mmol/L), or if total serum cholesterol concentrations fall below 140 mg/dL (3.6 mmol/L).

CONCOMITANT TREATMENT Lovastatin is effective alone or in combination with bile-acid sequestrants.

Page 1 of 11 In patients being given cyclosporine, danazol, gemfibrozil, other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin at the same time as lovastatin, the maximum recommended dose is 20 mg/day. In patients taking amiodarone or verapamil concomitantly with lovastatin, the dose of lovastatin should not exceed 40 mg/day (see section 4.4. Special warnings and precautions for use Myopathy/Rhabdomyolysis and 4.5. Interactions with other medicinal products and other forms of interaction)

DOSAGE IN RENAL INSUFFICIENCY Since lovastatin does not undergo significant renal excretion, moderate renal insufficiency does not necessitate any dosage reduction.

In patients with severe renal failure (creatinine clearance <30 ml/min) dosages over 20 mg/day should be carefully considered, and, if necessary, should be commenced with caution (see section 4.4. Special warnings and precautions for use Myopathy/Rhabdomyolysis and 5.0 Pharmacological properties).

USE IN CHILDREN AND ADOLESCENTS (< 18 YEARS): The use of lovastatin in children is not recommended, as safety and efficacy studies have not been established.

USE IN THE ELDERLY In a controlled trial of the treatment of patients in the over-sixty age group, the effects appeared to be identical to those in the remainder of the population and there was no marked increase in frequency of clinical or laboratory adverse findings.

4.3 Contraindications

 Hypersensitivity to lovastatin or to any of the excipients of the medicinal product.  Active liver disease or unexplained persistently elevated serum transaminase levels.  Cholestasis  Myopathy  Concomitant administration of potent CYP3A4 inhibitors (itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone).  Concomitant treatment with delavirdine, verapamil and amiodarone.  Pregnancy and lactation (see section 4.6).  Alcoholism

4.4 Special warnings and precautions for use

Myopathy/Rhabdomyolysis: Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

- The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:

Potent inhibitors of CYP3A4, e.g., mibefradil (a calcium antagonist of the tetralol type), itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone, particularly with higher doses of lovastatin (see

Page 2 of 11 section 4.5. Interaction with other medicinal products and other forms of interaction, CYP3A4 Interactions and 5.2. Pharmacokinetic properties).

Lipid-lowering drugs that can cause myopathy when given alone: Gemfibrozil, other fibrates, or lipid-lowering doses (_1 g/day) of niacin, particularly with higher doses of lovastatin (see section 4.5. Interaction with other medicinal products and other forms of interaction, Interactions with lipid-lowering drugs that can cause myopathy when given alone and 5.2. Pharmacokinetic properties).

Cyclosporine or danazol particularly with higher doses of lovastatin. (see section 4.5. Interaction with other medicinal products and other forms of interaction, Other drug interactions and 5.2. Pharmacokinetic properties).

Other drugs: Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class (see section 4.5. Interaction with other medicinal products and other forms of interaction, Other drug interactions).

Fusidic Acid: The risk of myopathy may be increased when fusidic acid is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see section 4.4. Special warnings and special precautions for use, Myopathy/Rhabdomyolysis and 5.2. “Pharmacokinetic properties”).

HMG-CoA inhibitors and antifungal medicinal products, which are azole derivatives, inhibit cholesterol synthesis at different points in the synthesis chain. Patients who are receiving cyclosporin treatment should have lovastatin therapy withdrawn if systemic fungicide treatment with an azole derivative is necessary. Patients who are not receiving cyclosporin treatment should be carefully monitored if systemic fungicide treatment with an azole derivative is necessary.

Lovastatin treatment must be temporarily interrupted or withdrawn in patients who have a condition which predisposes them to the development of renal failure, such as a serious acute infection, hypotension, major surgery, trauma, a severe metabolic, endocrine or electrolyte balance disorder or uncontrolled epilepsy. - As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.

Creatine Kinase measurement: Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5xULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment: All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Clinicians should prescribe statins with caution in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a creatine kinase (CK) level should be measured before starting statin treatment in the following situations: - Elderly (age >70 years)

Page 3 of 11 - Renal impairment - Uncontrolled hypothyroidism - Personal or familial history of hereditary muscular disorders - Previous history of muscular toxicity with a statin or fibrate - Alcohol abuse

In such situations the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If a patient has previously experiences a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated (> 5xULN) at baseline, treatment should not be started.

Whilst on treatment: If muscular pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (>5xULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are elevated to ≤ 5xULN, treatment discontinuation should be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

Therapy with lovastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Consequently: 1. Use of lovastatin concomitantly with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin, or telithromycin is unavoidable, therapy with lovastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.

2. The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with cyclosporine, danazol, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin. The combined use of lovastatin with gemfibrozil should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. The benefits of the use of lovastatin in patients receiving other fibrates, niacin, cyclosporine, or danazol should be carefully weighed against the risks of these drug combinations. Addition of fibrates or niacin to lovastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained. Combinations of fibrates or niacin with low doses of lovastatin have been used without myopathy in small, short-term clinical studies with careful monitoring.

3. The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.

4. Patients on fusidic acid and lovastatin should be closely monitored. Temporary suspension of lovastatin treatment may be considered.

Page 4 of 11 5. All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

6. Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

HEPATIC EFFECTS In the initial clinical trials, marked (to more than 3 times the ULN) increases in transaminases occurred in a few patients, usually appearing 3 to 12 months after the start of therapy with lovastatin, but without the development of jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. A liver biopsy was done in one of these patients and showed mild focal hepatitis. Some of these patients had abnormal liver function tests prior to lovastatin therapy and/or consumed substantial quantities of alcohol. In patients in whom the drug was interrupted or discontinued because of raised transaminases, including the patient who underwent liver biopsy, the transaminase levels fell slowly to pretreatment levels.

In the 48-week EXCEL study performed in 8,245 patients, the incidence of marked (more than 3 times the ULN) increases in serum transaminases on successive testing was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day and 1.5% at 80 mg/day in patients on lovastatin (see Section 5.0. Pharmacological properties).

It is recommended that liver function tests be performed before initiation of therapy in patients with a history of liver disease, or when otherwise clinically indicated, and also periodically later (e. g. every half year), particularly in patients whose results are abnormal and/or who consume high quantities of alcohol and/or who receive doses > 40 mg lovastatin/day. It is recommended that liver function tests be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated.

If the serum transaminase level rises higher than three times the upper limit of normal values, it is advisable to weigh the potential harm that may result from continuation of lovastatin treatment with the benefit that is assumed to be obtainable. The transaminase levels must be re-measured soon afterwards. If they remain high or rise even further, use of the medicinal product must be discontinued.

As with other lipid-lowering agents, moderate (less than three times the ULN) elevations of serum transaminases have been reported during therapy with lovastatin (see section 4.8. Undesirable effects). These changes appeared soon after initiation of therapy with lovastatin, were usually transient, and were not accompanied by any symptoms; interruption of treatment was not required.

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained persistent elevations of serum transaminases is a contraindication to the use of lovastatin (see section 4.3. Contrainidications).

Page 5 of 11 OPHTHALMIC EVALUATIONS The occurrence of lens opacities due to ageing may increase without any medicinal product treatment. The results of long-term clinical trials do not indicate that lovastatin has a harmful effect upon the lens in man.

INTERSTITIAL LUNG DISEASE Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8. Undesirable effects). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

PAEDIATRIC USE Safety and effectiveness of lovastatin in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least one year post-menarche. Patients treated with lovastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. (See section 4.2. Posolgy and method of administration, 4.8 Undesirable effects and 5.0. Pharmacological Properties) Adolescent females should be counseled on appropriate contraceptive methods while on lovastatin therapy (see section 4.3 Contraindications; 4.6. Pregnancy and Lactation). Lovastatin has not been studied in pre-pubertal patients or patients younger than 10 years of age.

ELDERLY In one controlled study in elderly patients over the age of 60, efficacy appeared similar to that seen in the population as a whole, and there was no apparent increase in the frequency of clinical or laboratory adverse findings.

HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA Lovastatin is not as effective as otherwise for patients who are suffering from rare homozygotic familial hypercholesteraemia. This may be due to the fact that these patients do not have functional LDL-receptors. Lovastatin appears more likely than usual to raise the serum transaminase levels (see section 4.8. Undesirable effects) in these homozygotic patients.

HYPERTRIGLYCERIDAEMIA Lovastatin lowers the triglyceride concentration only moderately, so that its use is not indicated in cases where hypertriglyceridaemia is the principal therapeutic indication (in hyperlipidaemia types I, IV and V).

VITAMIN K ANTAGONISTS There is a risk for increased effect of vitamin K antagonists (see section 4.5, sub-section coumarin derivatives).

IMPAIRED RENAL FUNCTION Lovastatin should be used with caution in severe renal impairment (creatinine clearance <30 ml/min) (See section 4.2).

SECONDARY HYPERCHOLESTEROLEMIA In case of secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, first treat the underlying disease.

Page 6 of 11 4.5 Interaction with other medicinal products and other forms of interaction

CYP3A4 Interactions Interactions associated with cytochrome P450 3A4. Lovastatin has no inhibitory effect on cytochrome P450 3A4. Therefore, lovastatin is not expected to influence the plasma concentrations of medicinal products metabolized via P450 3A4 cytochrome. However, lovastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 may increase the risk of myopathy by reducing the elimination of lovastatin.

Such inhibitors include: Mibefradil Itraconazole Ketoconazole Erythromycin Clarithromycin HIV protease inhibitors Nefazodone (see section 4.4. Special warnings and precautions for use, Myopathy/Rhabdomyoloysis and 5.2. Pharmacokinetic properties).

Interactions with lipid-lowering drugs that can cause myopathy when given alone The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent inhibitors of CYP3A4, but which can cause myopathy when given alone.

Gemfibrozil Other fibrates Niacin (nicotinic acid) at lipid-lowering doses (≥1 g/day) (see section 4.4. Special warnings and precautions for use, Myopathy/Rhabdomyolysis).

Co-administration of lovastatin and gemfibrozil led to a considerable increase in the concentration of the active metabolite in plasma in healthy volunteers compared with co- administration of lovastatin and placebo.

Other drug interactions Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of lovastatin (see section 4.4. Special warnings and precautions for use, Myopathy/Rhabdomyolysis and 5.2. Pharmacokinetic properties).

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is given concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class (see section 4.4 Special warnings and precautions for use, Myopathy/Rhabdomyolysis).

Other interactions Grapefruit juice contains one or more ingredients that inhibit cytochrome P450 3A4 and may therefore increase the plasma concentrations of medicinal products metabolized via cytochrome P450 3A4. The effect of typical consumption (one 250-ml glass daily) is minimal (34% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, very high quantities of grapefruit juice (more than a litre a day) significantly increase the inhibitory activity of HMG-CoA reductase during lovastatin therapy and such quantities should therefore be avoided (see section 4.4 Special warnings and precautions for use, Myopathy/Rhabdomyolysis).

Page 7 of 11 COUMARIN DERIVATIVES When lovastatin and coumarin derivatives are used concurrently, prothrombin time may be prolonged in some patients. In patients receiving anticoagulant therapy, prothrombin time should be determined before starting lovastatin therapy and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, it can be determined at the intervals usually recommended for patients receiving coumarin therapy. If the dose of lovastatin is changed, the same procedures should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not receiving anticoagulant therapy.

4.6 Pregnancy and lactation

Pregnancy: Lovastatin is contraindicated during pregnancy.

Safety in pregnant women has not been established. No controlled clinical trials with lovastatin have been carried out in pregnant women. There have been rare reports of congenital abnormalities following intrauterine exposure to HMG-CoA reductase inhibitors. In an analysis of approximately 200 prospectively followed pregnancies in women who were treated with lovastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital abnormalities was compared with the incidence in the population in general. The number of pregnancies was statistically adequate to exclude a 2.5-fold or greater increase in congenital abnormalities in relation to the general incidence.

Even though there are no signs of a difference in the incidence of congenital abnormalities in children born to patients who take lovastatin or another closely related HMG-CoA reductase inhibitor and the incidence in the population in general, treatment of the mother with lovastatin can reduce the fetal level of mevalonate, which is a precursor stage in cholesterol biosynthesis. Arteriosclerosis is a chronic process, and withdrawal of lipid-lowering agents during pregnancy probably has no noteworthy influence on the result of long-term treatment of primary hypercholesterolaemia. Lovastatin should therefore not be used in pregnant women, women who are trying to become pregnant, or if pregnancy is suspected. Treatment with lovastatin should be suspended during pregnancy or until it is established that the women is not pregnant (see section 4.3. Contraindications).

Lactation: It is not known whether lovastatin or its metabolites are excreted into breast milk. As many drugs are excreted into breast milk, and as there is a potential risk of serious undesirable effects, women taking lovastatin should not breast-feed.

4.7 Effects on ability to drive and use machines Lovastatin has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable effects Lovastatin is generally well tolerated; the adverse reactions of lovastatin have for the most part been mild and transient.

The frequency of adverse reactions can be ranged as follows: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data).

Page 8 of 11 The following table below lists the adverse effects based on data derived from clinical studies and from post-marketing experience.

Immune system disorders Rare (≥1/10,000 to <1/1,000) Hypersensitivity syndrome associated with one or more of the following symptoms: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, leucopenia, eosinophilia, haemolytic anaemia, positive antinuclear antibodies (ANA), increased sedimentation rate, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, flushes, chills, dyspnoea and malaise.

Metabolism and nutrition disorders Common (≥ 1/100 to <1/10) Digestive disorders. Rare (≥ 1/10.000 to < 1/1000) Anorexia. Psychiatric disorders Uncommon (≥ 1/1000 to < 1/100) Insomnia, sleeping difficulties. Rare (≥ 1/10.000 to < 1/1000) Psychological disturbances including restlessness/anxiety. Not known Depression. Nervous system disorders common (≥ 1/100 to <1/10) Vertigo, cephalagia. uncommon (≥ 1/1000 to < 1/100) Dysgeusia. Rare (≥ 1/10.000 to < 1/1000) Peripheral neuropathy, in particular if used for a long period of term, paraesthesia. Not known Memory impairment. Eye disorders Common (≥ 1/100 to <1/10) Blurred vision.

Gastrointestinal disorders Common (≥ 1/100 to <1/10) Flatulence, diarrhoea, constipation, nausea, dyspepsia, abdominal pains. Rare (≥ 1/10.000 to < 1/1000) Vomiting.

Hepatobiliary disorders Rare (≥ 1/10.000 to < 1/1000) Hepatitis, cholestatic jaundice. Skin and subcutaneous tissue disorders Common (≥ 1/100 to <1/10) Rash. Uncommon (≥ 1/1000 to < 1/100) Pruritus, xerostomia. Rare (≥ 1/10.000 to < 1/1000) Hair loss, toxic epidermal necrolysis and erythema multiforme including Stevens-Johnson syndrome. Musculoskeletal and connective tissue disorders Common (≥ 1/100 to <1/10) Muscle cramps and myalgia. Rare (≥ 1/10.000 to < 1/1000) Myopathia and rhabdomyolysis, erectile dysfunction. General disorders and administration site conditions Uncommon (≥ 1/1000 to < 1/100) Tiredness.

Page 9 of 11 Investigations Rare (≥ 1/10.000 to< 1/1000) Marked and persistent increases in serum transaminase concentrations (see section 4.4. Special warnings and precautions for use). Other irregularities in liver function tests, including elevated alkaline phosphatase and bilirubin have been reported. Increases in the serum concentration of CK (which may be attributed to the non-cardiac fraction of CK) have been seen. These have usually been slight and transient; marked increases have only occurred in rare cases (see section 4.4. Special warnings and precautions for use, Myopathy/Rhabdomyolysis).

In the 48-week expanded clinical evaluation of lovastatin (EXCEL study) comparing lovastatin to placebo, the adverse experiences reported were similar to those of the initial studies, and the incidence on drug and placebo was not statistically different.

The following additional adverse events have been reported with some statins: - Sleep disturbances, including nightmares - Memory loss - Sexual dysfunction - Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4. Special warnings and precautions for use)

PAEDIATRIC PATIENTS (AGES 10-17 YEARS) In a 48-week controlled study in adolescent boys with heterozygous familial hypercholesterolemia (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heterozygous familial hypercholesterolemia (n=54), the safety and tolerability profile of the groups treated with lovastatin (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see section 4.4. Special warnings and precautions for use and 5.0. Pharmacological properties).

4.9 Overdose Until further experience with overdose of lovastatin has been obtained, no specific treatment can be recommended. General measures for overdose should be applied and liver function should be monitored.

The dialysability of lovastatin and its metabolites is not known at present.

Five healthy volunteers received up to 200 mg lovastatin as a single dose without clinically significant adverse effects. A few cases of accidental overdose have been reported. None of the patients had specific symptoms, and all recovered without sequelae. The highest dose was 5-6 g.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Serum lipid reducing agents- HMG CoA reductase inhibitors. ATC code: C10 AA 02 Lovastatin, which is an inactive lactone, is hydrolysed after oral administration to the corresponding -hydroxyacid. This is the major metabolite and an inhibitor of 3-hydroxy-3-

Page 10 of 11 methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyses an early and rate-limiting step in the biosynthesis of cholesterol. In clinical trials lovastatin reduced the plasma concentration of total cholesterol and of LDL- and VLDL-cholesterol (low-density and very low-density lipoproteins) and also increased HDL-cholesterol (high-density lipoproteins) and reduced plasma triglycerides.

The active form of lovastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate. As the conversion of HMG-CoA to mevalonate is an early step in the biosynthesis of cholesterol, treatment with lovastatin is thought not to cause accumulation of any toxic sterols. Moreover, HMG-CoA is rapidly converted to acetyl-CoA, which is involved in many biosynthetic processes in the body.

5.2 Pharmacokinetic properties In animal studies lovastatin, after oral administration, has displayed high selectivity for the liver, where lovastatin can be measured in far higher concentrations than in other tissues. Lovastatin undergoes extensive first-pass metabolism in the liver, the substance’s primary site of action, with subsequent excretion in the bile. After oral administration of lovastatin to trial subjects 10 % of the dose was excreted in the urine and 83 % in the faeces. Both lovastatin and its beta-hydroxyacid are bound to human plasma proteins (>95 %). Animal studies have shown that lovastatin crosses the blood/brain barrier and the placental barrier. Peak plasma concentrations of lovastatin and its active metabolites are reached in the course of 2-4 hours after administration. Linear plasma concentrations are seen up to a dosage of 120 mg lovastatin. With daily administration, steady state in plasma concentrations is reached after 2-3 days. When administered when fasting, concentrations of lovastatin and active metabolites corresponded to 2/3 of the plasma concentration obtained when administered immediately after a normal meal. The risk of myopathy is increased in cases of high concentrations of HMG-CoA reductase inhibitor activity in plasma. Potent inhibitors of CYP3A4 can increase the plasma concentration of HMG-CoA reductase inhibitor activity and increase the risk of myopathy (see section 4.4 muscular effects and 4.5).

5.3 Preclinical safety data The repeated administration of lovastatin in high doses led to toxic effects in various animal species, which were attributable to an excessive pharmacological action. The main target organs were the liver and the CNS. In studies on dogs cataracts occurred in isolated cases after the administration of lovastatin in the high dose range; however, on the basis of AUC levels there seems to be a sufficiently high safety margin in relation to the human therapeutic dose.

No evidence of a genotoxic potential was found in a battery of (in-vitro and in-vivo) genetic toxicology studies.

An increased incidence of tumours (e.g. Hepatocellular carcinomas and adenomas, Pulmonary adenomas, and Papillomas in squamous epithelium of the gastric mucosa) was observed after the administration of lovastatin in long-term studies on mice and rat carried out to detect a tumorigenic potential.

The significance of these findings for long-term therapy in humans is still unclear.

In reproduction toxicology studies skeletal malformations occurred in the foetuses after the administration of high dosages (800 mg/kg/day) to rats and mice. In rabbits no malformations were observed in the offspring with dosages of up to 15 mg/kg/day (MTD). Fertility was impaired in dogs with dosages from 20 mg/kg/day, but a fertility study in rats proved negative.

Page 11 of 11 6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients 20 mg Pregelatinised starch, microcrystalline cellulose, magnesium stearate, butylated hydroxyanisole (E 320), indigo carmine (E 132). 40 mg Pregelatinised starch, microcrystalline cellulose, magnesium stearate, butylated hydroxyanisole (E 320), indigo carmine (E 132), quinoline yellow (E 104).

6.2 Incompatibilities Not applicable.

6.3 Shelf-life 2 years.

6.4 Special precautions for storage This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container Aluminium/aluminium blister. Pack sizes: 10, 28, 30, 50, 100. Not all pack sizes may be marketed.

6.6 Instructions for use/handling No special requirements.

7. MARKETING AUTHORISATION HOLDER

Mylan AB

8. MARKETING AUTHORISATION NUMBERS

20 mg: 32379 40 mg: 32380

9. DATE OF FIRST AUTHORISATION

10. DATE OF REVISION OF THE TEXT

January 2012

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